In the recently issued United States Patent No. 3,843,682 there is disclosed a process for preparing 3-methyl-2-(2-chlorosulfinyl-4-oxo-3-imido-1-azetidinyl)-3-butenoate esters, variously termed "2-chlorosulfinyl-3-imido-azetidin-4-ones". These compounds are prepared from the corresponding penicillin sufloxide esters by reaction of the latter with sulfuryl chloride at a temperature of from about 75.degree. C. to about 120.degree. C. The compounds which are prepared by this known process are exclusively the 3-imido substituted 2-chlorosulfinylazetidin-4-ones since the process is limited to the use of the 6-imido penicillin sulfoxide esters as starting material. There is no disclosure of the use of or the possibility to use the 6-amido penicillin sulfoxide esters, including the conveniently obtainable penicillin sulfoxide derivatives of the naturally occurring Penicillin G and/or Penicillin V. When one attempts to carry out the reaction disclosed in U.S. Pat. No. 3,843,682 using a 6-amido penicillin sulfoxide ester as starting material, the product which is obtained is a complex mixture containing no 2-chlorosulfinylazetidin-4-one product, or, at most, the latter in a quantity so minute as to be undetectable by ordinary analytical techniques. Therefore, this previously disclosed method has significant deficiencies since it requires the absence of an amide hydrogen in the 6-position of the penicillin sulfoxide starting material.
In co-pending Application Ser. No. 673,017 filed Apr. 2, 1976, a method for preparing sulfinyl chloride intermediates from 6-amido penicillin sulfoxide esters is provided. This method involves treating the penicillin sulfoxide with an N-chloro halogenating agent at a temperature of from about 75.degree. C. to about 135.degree. C.
It now has become apparent that the degree of conversion of the 6-amido penicillin sulfoxide to the sulfinyl chloride in accordance with the reaction described in application Ser. No. 673,017 diminishes considerably when the reaction scale is increased beyond typical research laboratory quantities, for example, in those instances in which 50 grams or more of the penicillin sulfoxide starting material are employed.
This invention is directed to the discovery that, in a large scale reaction (about 100 millimoles or more), the extent of conversion of a 6-amido penicillin sulfoxide to its corresponding sulfinyl chloride can be substantially increased by carrying out the reaction under specified conditions.
The 2-chlorosulfinylazetidin-4-ones produced by the process of this invention can be ring closed to produce a 3-exomethylenecepham sulfoxide ester. Cyclization of the 2-chlorosulfinylazetidin-4-ones to their corresponding 3-exomethylenecepham sulfoxides is accomplished by a Friedel-Crafts catalyst induced intramolecular reaction involving the sulfinyl chloride and the olefinic moieties of the azetidin-4-one starting material. This reaction generally is carried out using stannic chloride as Friedal-Crafts catalyst.